Polysubstituted and fused pyridines are widely used chemicals. They are pharmaceutical active ingredients, biological markers, and starting ingredients in pharmaceutical synthesis. Unfortunately, however, it is difficult to synthesize them in high yields. Pyridines substituted at the 2, 3, 4 and 2, 3, 4, 5 positions are particularly valuable, but very few of the conventional techniques for pyridine substitution actually lead to 2, 3, 4 or 2, 3, 4, 5 substituted pyridines.

Baldwin, Raab, and Ponticello (BRP) previously developed a scheme to synthesize substituted 2-bromonicotinonitriles from alkylidene malononitriles using N,N-dimethylformamide dimethyl acetal (DMF-DMA). Scheme 1 illustrates the BRP synthesis from an alkylidene malononitrile to a 4,5-substituted-2-bromonicotinonitrile.

The BRP synthesis works, but the yield is not ideal for synthesis of nicotinonitriles in commercial yields. We ascribe the yield of the BRP synthesis to dimerization of the alkylidene malononitrile starting ingredient.